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Systems analysis of protective immune responses to RTS,S malaria vaccination in humans.

ABSTRACT: RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ?50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.

SUBMITTER: Kazmin D

PROVIDER: S-EPMC5338562 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Systems analysis of protective immune responses to RTS,S malaria vaccination in humans.

Kazmin Dmitri D Nakaya Helder I HI Lee Eva K EK Johnson Matthew J MJ van der Most Robbert R van den Berg Robert A RA Ballou W Ripley WR Jongert Erik E Wille-Reece Ulrike U Ockenhouse Christian C Aderem Alan A Zak Daniel E DE Sadoff Jerald J Hendriks Jenny J Wrammert Jens J Ahmed Rafi R Pulendran Bali B

Proceedings of the National Academy of Sciences of the United States of America 20170213 9

RTS,S is an advanced malaria vaccine candidate and confers significant protection against <i>Plasmodium falciparum</i> infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsp ...[more]

PMID: 28193898

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Project description:BackgroundThe RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the antibodies associated with protection against clinical malaria in young African children participating in the multicenter phase 3 trial for licensure.MethodsWe measured total IgM, IgG, and IgG1-4 subclass antibodies to three constructs of the Plasmodium falciparum circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in Ghana (Kintampo) and Mozambique (Manhiça) with different transmission intensities using a case-control study design. We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and factors affecting them.ResultsRTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses. Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated with protection. Age and site affected the relative contribution of responses in the correlates identified.ConclusionsCytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of vaccine success and failure in African children and reveal key insights into the mode of action that can guide development of more efficacious next-generation vaccines.

Project description:Naturally acquired immunity (NAI) to Plasmodium falciparum malaria is mainly mediated by IgG antibodies but the subclasses, epitope targets and effector functions have not been unequivocally defined. Dissecting the type and specificity of antibody responses mediating NAI is a key step toward developing more effective vaccines to control the disease. We investigated the role of IgG subclasses to malaria antigens in protection against disease and the factors that affect their levels, including vaccination with RTS,S/AS01E. We analyzed plasma and serum samples at baseline and 1 month after primary vaccination with RTS,S or comparator in African children and infants participating in a phase 3 trial in two sites of different malaria transmission intensity: Kintampo in Ghana and Manhiça in Mozambique. We used quantitative suspension array technology (qSAT) to measure IgG1-4 responses to 35 P. falciparum pre-erythrocytic and blood stage antigens. Our results show that the pattern of IgG response is predominantly IgG1 or IgG3, with lower levels of IgG2 and IgG4. Age, site and RTS,S vaccination significantly affected antibody subclass levels to different antigens and susceptibility to clinical malaria. Univariable and multivariable analysis showed associations with protection mainly for cytophilic IgG3 levels to selected antigens, followed by IgG1 levels and, unexpectedly, also with IgG4 levels, mainly to antigens that increased upon RTS,S vaccination such as MSP5 and MSP1 block 2, among others. In contrast, IgG2 was associated with malaria risk. Stratified analysis in RTS,S vaccinees pointed to novel associations of IgG4 responses with immunity mainly involving pre-erythrocytic antigens upon RTS,S vaccination. Multi-marker analysis revealed a significant contribution of IgG3 responses to malaria protection and IgG2 responses to malaria risk. We propose that the pattern of cytophilic and non-cytophilic IgG antibodies is antigen-dependent and more complex than initially thought, and that mechanisms of both types of subclasses could be involved in protection. Our data also suggests that RTS,S efficacy is significantly affected by NAI, and indicates that RTS,S vaccination significantly alters NAI.

Project description:BackgroundThe RTS,S/ASO1E malaria vaccine is being piloted in three countries-Ghana, Kenya, and Malawi-as part of a coordinated evaluation led by the World Health Organization, with support from global partners. This study estimates the costs of continuing malaria vaccination upon completion of the pilot evaluation to inform decision-making and planning around potential further use of the vaccine in pilot areas.MethodsWe used an activity-based costing approach to estimate the incremental costs of continuing to deliver four doses of RTS,S/ASO1E through the existing Expanded Program on Immunization platform, from each government's perspective. The RTS,S/ASO1E pilot introduction plans were reviewed and adapted to identify activities for costing. Key informant interviews with representatives from Ministries of Health (MOH) were conducted to inform the activities, resource requirements, and assumptions that, in turn, inform the analysis. Both financial and economic costs per dose, cost of delivery per dose, and cost per fully vaccinated child (FVC) are estimated and reported in 2017 USD units.ResultsAt a vaccine price of $5 per dose and assuming the vaccine is donor-funded, our estimated incremental financial costs range from $1.70 (Kenya) to $2.44 (Malawi) per dose, $0.23 (Malawi) to $0.71 (Kenya) per dose delivered (excluding procurement add-on costs), and $11.50 (Ghana) to $13.69 (Malawi) per FVC. Estimates of economic costs per dose are between three and five times higher than financial costs. Variations in activities used for costing, procurement add-on costs, unit costs of per diems, and allowances contributed to differences in cost estimates across countries.ConclusionCost estimates in this analysis are meant to inform country decision-makers as they face the question of whether to continue malaria vaccination, should the intervention receive a positive recommendation for broader use. Additionally, important cost drivers for vaccine delivery are highlighted, some of which might be influenced by global and country-specific financing and existing procurement mechanisms. This analysis also adds to the evidence available on vaccine delivery costs for products delivered outside the standard immunization schedule.

Dataset Information

Systems analysis of protective immune responses to RTS,S malaria vaccination in humans.

Publications

Systems analysis of protective immune responses to RTS,S malaria vaccination in humans.

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